Generalized metaphyseal modification with cone-shaped epiphyses following long-term administration of 13-cis-retinoic acid.

UNLABELLED: We report on a 6-year-old girl with short stature which developed following the administration of 13-cis-retinoic acid (a synthetic derivative of vitamin A or retinoid) for 40 months as adjunct chemotherapy for neuroblastoma. Radiographic examination suggested osteophyte formation in the cervical spine, which is the most common skeletal manifestation of retinoid toxicity [10, 11]. In addition, severe metaphyseal cupping with a cone-shaped epiphysis primarily affecting rapidly growing long bones was found, which represented impaired enchondral ossification. This epi-metaphyseal alteration, though unusually severe, was reminiscent of the premature epiphyseal closure which has been described as an adverse effect of 13-cis-retinoic acid [10-12]. Other minor skeletal changes included posterior scalloping of the vertebral bodies and increased interpediculate distances, which were related to a widened spinal canal found on CT. A literature search disclosed several primary skeletal dysplasias with superficial radiological similarities to those of the present patient. However, these entities showed significant clinical and radiological differences from our patient. CONCLUSION: The precise cause of the generalized skeletal alteration in the present patient remained unknown, but it conceivably resulted from the administration of 13-cis-retinoic acid.

Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis.

A study was conducted to investigate the cumulative survival rates among groups of patients with liver cirrhosis who were stratified by plasma branched-chain amino acid (BCAA)/aromatic amino acid (AAA) molar ratio (BCAA/AAA), and to evaluate the effect of long-term oral supplementation with BCAA on the prognosis of cirrhotics with noticeably lower BCAA/AAA molar ratio. When 104 patients with liver cirrhosis were divided into three groups on the basis of BCAA/AAA molar ratio, i.e., BCAA/AAA greater than or equal to 1.8 (Group 1), 1.8 greater than or equal to BCAA/AAA greater than or equal to 1.0 (Group 2), and 1.0 greater than BCAA/AAA (Group 3), Group 1 showed the highest cumulative survival rate, followed, respectively, by Groups 2 and 3 (P less than 0.05). In 20 cases of non-alcoholic liver cirrhosis having BCAA/AAA less than 1.8, oral supplementation with branched-chain amino acid granules (BCAA-G) for 6 months or more (median 27 months, range 7-62 months) brought about significant increase of plasma BCAA concentration, BCAA/AAA molar ratio, and serum albumin concentration. Furthermore, the 20 cases with BCAA-G supplementation showed significantly higher cumulative survival rate during 2-4 years as compared to the control cases matched for age, sex, and etiology (involvement of hepatitis B virus). These findings indicate that long-term oral supplementation with BCAA to cirrhotic patients provides beneficial effect on the prognosis by improving protein malnutritional status and consequently delaying fatal complications such as hepatic failure and gastrointestinal bleeding.

The follow up study of intra-arterial infusion chemotherapy with local vein blocking as a surgical neo-adjuvant treatment for locally advanced breast cancer.

Preoperative intra-arterial infusion neo-adjuvant chemotherapy, in combination with local vein blocking, was administered to thirty-one patients with locally advanced stage III breast cancer. The anti-cancer drugs and dosages used were 500 mg of 5-Fluorouracil (5FU), which was infused daily for 7-14 days, and 20 mg of Adriamycin (ADM), which was administered as a bolus dose twice into the subclavian and internal mammary arteries. The response rate of this method on the primary tumor was 48.4 per cent, and, histologically it was found to be as high as 90.3 per cent. The response rate of the clinical effects on the regional lymph nodes was 50.0 per cent, however, histologically, it was found to be lower than that of the primary tumor. In the long-term follow-up study the 5-year survival rate was 72.2 per cent. Thus, this method seems to be effective as a combined modality in cases of locally advanced stage III breast cancer.

Synthesis and antitumor activity of tropolone derivatives. 4.

Modifications of monotropolone 2 having poor potency against P388 in mice were studied. The alpha-ethoxy group of 2, prepared from hinokitiol and benzaldehyde diethyl acetal, was replaced with a phenolic or heteroaromatic compound by heating 2 with the appropriate nucleophile. Structure-activity relationships indicated that an acidic hydroxyl and a proton-accepting group situated in the neighboring position, which permits the formation of a chelate with a metal ion, contributed to enhanced activity. Among the compounds studied, the 8-hydroxyquinoline analogue 10f was the most favorable compound.

Synthesis and antitumor activity of tropolone derivatives. 3.

As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed high potency in the P388 leukemia assay. 4-Hydroxy analogue 4d showed the most potent activity (T/C = 195%) at a 5 mg/kg dose. The introduction of large-size substituents, of which the steric influence prevents coplanarity of the substituted aromatic function, resulted in a remarkable decrease in the potency. X-ray structural analysis of highly potent 4-methoxy analogue 4b was undertaken.

Synthesis and antitumor activity of tropolone derivatives.

Treatment of tropolones with benzaldehyde diethyl acetals gave monotropolone (12) and bistropolone (13) derivatives at the benzylic position, whereas the related 1-ethoxyisochroman and the diethyl acetals of crotonaldehyde and cinnamaldehyde gave only the monotropolone derivatives (5, 10, or 11). The monotropolone derivatives (5, 10, 11, and 12) had poor potency against P388 leukemia in mice, but the bistropolone derivatives (13 and 14) showed significant potency and prolongation of life.